X-54116649-G-C

Variant names:

• chrX-54116649-G-C
• rs1557126651
• NM_017848.6:c.2208C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017848.6(FAM120C):​c.2208C>G​(p.Asn736Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: FAM120C NM_017848.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

Genes affected

FAM120C (HGNC:16949): (family with sequence similarity 120 member C) This gene encodes a potential transmembrane protein and lies in a region where mutations and deletions have been associated with intellectual disability and autism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20029825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120C	NM_017848.6	c.2208C>G	p.Asn736Lys	missense_variant	Exon 10 of 16	ENST00000375180.7	NP_060318.4
FAM120C	NM_001300788.2	c.2208C>G	p.Asn736Lys	missense_variant	Exon 10 of 14		NP_001287717.1
FAM120C	XM_006724589.5	c.2208C>G	p.Asn736Lys	missense_variant	Exon 10 of 15		XP_006724652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120C	ENST00000375180.7	c.2208C>G	p.Asn736Lys	missense_variant	Exon 10 of 16	1	NM_017848.6	ENSP00000364324.2
FAM120C	ENST00000328235.4	c.2208C>G	p.Asn736Lys	missense_variant	Exon 10 of 14	1		ENSP00000329896.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 111839 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33987 FAILED QC

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000894 AC: 1 AN: 111839 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33987

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2208C>G (p.N736K) alteration is located in exon 10 (coding exon 10) of the FAM120C gene. This alteration results from a C to G substitution at nucleotide position 2208, causing the asparagine (N) at amino acid position 736 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	21
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.035
Sift	Benign	0.28	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.15	.;B
Vest4		0.20
MutPred		0.26		Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);
MVP		0.37
MPC		0.93
ClinPred		0.69	D
GERP RS		3.6
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557126651; hg19: chrX-54143082;